Leishmanicidal activity of isoselenocyanate derivatives

Celia Fernández-Rubio, Esther Larrea, José Peña Guerrero, Eduardo Sesma Herrero, Iñigo Gamboa, Carlos Berrio, Daniel Plano, Shantu Amin, Arun Sharma, Paul A. Nguewa

Research output: Contribution to journalArticle

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Abstract

Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania. In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G 1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

Original languageEnglish (US)
Article numbere00904-18
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number2
DOIs
StatePublished - Feb 1 2019

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Leishmania major
Leishmaniasis
Leishmania
Amphotericin B
Cell Cycle
Sulfur Compounds
Gastrin-Secreting Cells
Proliferating Cell Nuclear Antigen
Peritoneal Macrophages
Selenium
S Phase
Drug Resistance
Pharmaceutical Preparations
Antineoplastic Agents
Flow Cytometry
Parasites
Macrophages
Drug Therapy
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Fernández-Rubio, C., Larrea, E., Guerrero, J. P., Herrero, E. S., Gamboa, I., Berrio, C., ... Nguewa, P. A. (2019). Leishmanicidal activity of isoselenocyanate derivatives. Antimicrobial agents and chemotherapy, 63(2), [e00904-18]. https://doi.org/10.1128/AAC.00904-18
Fernández-Rubio, Celia ; Larrea, Esther ; Guerrero, José Peña ; Herrero, Eduardo Sesma ; Gamboa, Iñigo ; Berrio, Carlos ; Plano, Daniel ; Amin, Shantu ; Sharma, Arun ; Nguewa, Paul A. / Leishmanicidal activity of isoselenocyanate derivatives. In: Antimicrobial agents and chemotherapy. 2019 ; Vol. 63, No. 2.
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abstract = "Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania. In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G 1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.",
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Fernández-Rubio, C, Larrea, E, Guerrero, JP, Herrero, ES, Gamboa, I, Berrio, C, Plano, D, Amin, S, Sharma, A & Nguewa, PA 2019, 'Leishmanicidal activity of isoselenocyanate derivatives', Antimicrobial agents and chemotherapy, vol. 63, no. 2, e00904-18. https://doi.org/10.1128/AAC.00904-18

Leishmanicidal activity of isoselenocyanate derivatives. / Fernández-Rubio, Celia; Larrea, Esther; Guerrero, José Peña; Herrero, Eduardo Sesma; Gamboa, Iñigo; Berrio, Carlos; Plano, Daniel; Amin, Shantu; Sharma, Arun; Nguewa, Paul A.

In: Antimicrobial agents and chemotherapy, Vol. 63, No. 2, e00904-18, 01.02.2019.

Research output: Contribution to journalArticle

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T1 - Leishmanicidal activity of isoselenocyanate derivatives

AU - Fernández-Rubio, Celia

AU - Larrea, Esther

AU - Guerrero, José Peña

AU - Herrero, Eduardo Sesma

AU - Gamboa, Iñigo

AU - Berrio, Carlos

AU - Plano, Daniel

AU - Amin, Shantu

AU - Sharma, Arun

AU - Nguewa, Paul A.

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N2 - Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania. In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G 1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

AB - Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania. In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G 1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

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Fernández-Rubio C, Larrea E, Guerrero JP, Herrero ES, Gamboa I, Berrio C et al. Leishmanicidal activity of isoselenocyanate derivatives. Antimicrobial agents and chemotherapy. 2019 Feb 1;63(2). e00904-18. https://doi.org/10.1128/AAC.00904-18